1. Field of the Invention
This invention relates to chemical compounds which are antibacterial agents of the type called aminoglycosides and includes chemical processes for their production.
2. Description of the Prior Art
It has been elucidated that drug-resistant bacteria which have been isolated from patients, such as drug-resistant Staphylococcus aureaus, drug-resistant Escherichia coli and Pseudomonas aeruginosa exhibit resistance to Kanamycins by the mechanism that these microorganisms produce phosphotransferase capable of phosphorylating the 3'-hydroxyl group of kanamycins and inactivate these antibiotics. (see the "Science" Vol. 157, page 1559, (1967).
On the basis of this mechanism of resistance of the drug-resistant bacteria, we have considered it possible to produce semi-synthetic antibiotics which are active against kanamycin-resistant bacteria. Thus, we and our colleagues synthesized 3'-deoxykanamycin A (see U.S. Pat. No. 3929761); 3',4'-dideoxykanamycin B (hereinafter abbreviated as DKB) (see Japanese Pat. publication No. 7595/75 and U.S. Pat. No. 3753973); 3'-deoxykanamycin B and 3'-deoxyribostamycin (see U.S. Pat. No. 3929762). It has been found that these deoxy derivatives of aminoglycosidic antibiotics exhibit high antibacterial activity against the above-mentioned resistant bacteria. It has been confirmed that DKB is a very useful and effective semi-synthetic antibiotic in clinical tests.
Furthermore, it has been concluded that a few of drug-resistant gram-negative bacterial (including Escherichia coli carrying R-factor) produces a kanamycin-inactivating enzyme capable of nucleotidylating the 2"-hydroxy group of kanamycin and DKB (see the "Journal of Antibiotics" Vol. 25, page 492 (1972) Considering the molecular configuration of kanamycins, we have expected it possible to create such derivatives of aminoglycosidic antibiotics which are not attached by the enzymatic reactions of the kanamycin-inactivating enzymes, if some change occurs in the molecule of kanamycins by modifying the 1-amino group of kanamycins and their analogous aminoglycosdic antibiotics. With this expectation, we and our colleagues have made further research to semi-synthetize various derivatives of aminoglycosidic antibiotics. Thus, 1-N-(4-amino-2-hydroxybutyryl)-DKB; 1-N-(4-amino-2-hydroxybutyryl)-kanamycin; 1-N-isoserylkanamycin; 1-N-isoserylkanamycin B and 1-N-isoseryl-DKB which are active against the kanamycin-resistant bacteria have been synthesized (see British Pat. No. 1426908).
Moreover, we and our colleagues have synthetized such kanamycin B derivatives by acylating both the 1-amino and 2'-amino groups of kanamycin B or DKB with an .alpha.-hydroxyamino acid of the formula H.sub.2 N--(CH.sub.2).sub.n --CH(OH)--COOH wherein n is an integer of 1 or 2 (see U.S. Pat. No. 3940382). It has been confirmed that these semi-synthetic kanamycin B derivatives of this type exhibit a high antibacterial activity not only against the kanamycin-sensitive but also kanamycin-resistant bacteria including Pseudomonas aeruginosa and which are of a low toxicity.
We have previously proposed some methods of synthetizing a 1-N-(.alpha.-substituted-.beta.-aminoalkanoyl)-3'-deoxyribostamycin (see British Pat. No. 2426908 and co-pending Japanese patent application No. 49107/75, co-pendng U.S. Pat. application Ser. No. 676,792 filed on Apr. 14, 1976).